title: A computational model for overcoming drug resistance using selective dual-inhibitors for aurora kinase A and its T217D variant.
abstract: The human Aurora kinase-A (AK-A) is an essential mitotic regulator that is frequently overexpressed in several cancers. The recent development of several novel AK-A inhibitors has been driven by the well-established association of this target with cancer development and progression. However, resistance and cross-reactivity with similar kinases demands an improvement in our understanding of key molecular interactions between the Aurora kinase-A substrate binding pocket and potential inhibitors. Here, we describe the implementation of state-of-the-art virtual screening techniques to discover a novel set of Aurora kinase-A ligands that are predicted to strongly bind not only to the wild type protein, but also to the T217D mutation that exhibits resistance to existing inhibitors. Furthermore, a subset of these computationally screened ligands was shown to be more selective toward the mutant variant over the wild type protein. The description of these selective subsets of ligands provides a unique pharmacological tool for the design of new drug regimens aimed at overcoming both kinase cross-reactivity and drug resistance associated with the Aurora kinase-A T217D mutation.
authors.affiliation: Li Ka Shing Applied Virology Institute, Department of Medical Microbiology and Immunology, ‡Department of Oncology, and §Department of Physics, University of Alberta , Edmonton, Alberta P6G 2M7, Canada.
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Barakat
authors.forename: J Torin
authors.initials: JT
authors.lastname: Huzil
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Jordan
authors.forename: Constantinos
authors.initials: C
authors.lastname: Evangelinos
authors.forename: Michael
authors.initials: M
authors.lastname: Houghton
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
mesh_terms: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics*; D003198:Computer Simulation; D004351:Drug Resistance / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D064096:Aurora Kinase A